Atherosclerosis—the deposition of lipid in the intima of large or medium-sized arteries, with accompanying fibrosis—is the major cause of arterial disease in the United States (Chapter 20: The Blood Vessels). Thrombosis occurs in atherosclerotic arteries. It represents the most common cause of arterial obstruction and is the leading cause of death in the United States. Narrowing or occlusion of the coronary and cerebral arteries is responsible for myocardial infarction (heart attack) and cerebral infarction (stroke), respectively. Over 4 million Americans have clinically evident atherosclerosis; Americans suffer 1.25 million heart attacks and 500,000 strokes each year. Over 800,000 of these episodes are fatal, representing 40% of all deaths in the United States. Similar statistics apply to Western Europe; a much lower incidence is seen in developing countries.
Effect of Arterial Obstruction
The effect of arterial obstruction on a tissue is governed by the degree of reduction of blood flow to the tissue in relation to its metabolic needs. Tissue changes resulting from arterial obstruction are influenced by several factors.
Availability of Collateral Circulation
(Figure 9-1.) Collateral circulation varies between two extremes: In tissues with a rich collateral arterial supply, blood flow is not significantly decreased by occlusion of one artery (Figure 9-1A); eg, radial artery occlusion does not produce ischemia in the hand because the collateral ulnar artery circulation will compensate. In tissues with no collateral arterial supply, obstruction of the end artery supplying the tissue leads to complete cessation of blood flow and infarction (Figure 9-1B), eg, the central artery of the retina or the middle cerebral artery.
Effect of arterial obstruction on tissues. A: Loop of intestine supplied by 3 arteries. Obstruction of the major supply artery has no effect on the tissue because normal blood flow is maintained by collaterals. B: The sole artery of blood supply to the retina is the central retinal artery (which is therefore an end artery), obstruction of which causes retinal infarction. C: The posterior wall of the left ventricle is supplied by both left and right coronary arteries. Obstruction of the major supplying artery is partially compensated for by increased flow in collaterals. The exact effect depends on several other factors (see text). In the example shown, the tissue has suffered a reduction in blood flow that has resulted in chronic ischemia with atrophy of myocardial fibers and fibrosis.
When the availability of a collateral arterial circulation falls between these two extremes (Figure 9-1C), the result of arterial obstruction depends on the other factors discussed in the succeeding paragraphs.
Integrity of Collateral Arteries
Narrowing of arteries in the collateral circulation obviously decreases their effectiveness. Occlusion of the internal carotid artery in a healthy young adult is usually compensated for by increased flow in the collaterals in the circle of Willis. However, in older people with atherosclerotic narrowing of these collateral arteries, ischemia to the brain frequently occurs when one internal carotid artery is occluded.
Ischemic changes in tissues that normally have a barely adequate collateral circulation (eg, intestine and extremities) are much more common in older patients as a direct result of the widespread occurrence of significant atherosclerosis in the elderly.
Rate of Development of Obstruction
Sudden arterial obstruction produces more severe ischemic changes than does gradual occlusion because there is less time for enlargement of potential collateral vessels. For example, sudden occlusion of a previously normal coronary artery leads to myocardial infarction. More gradual occlusion of the same artery produces less ischemic myocardial change because collateral vessels have more time to develop.
Tissue Susceptibility to Ischemia
Tissues differ in their ability to withstand ischemia. Brain and heart are highly susceptible, and infarction (ischemic necrosis) occurs within minutes after arterial occlusion. In contrast, skeletal muscle, bone, and certain other tissues can withstand several hours of ischemia before changes occur. Emergency surgery performed on an occluded brachial or femoral artery can therefore prevent major infarction in an extremity.
Cooling slows the rate of development of ischemic damage because of a general decrease in the tissue's metabolic requirements. This phenomenon is exploited in hypothermia deliberately induced in some types of surgery and in cooling of individual organs that are to be transported for transplantation.
While veins become obstructed frequently, venous obstruction is less of a problem clinically. This is because of the generally much greater availability of collateral vessels in the venous system than in the arterial system.
Effect of Venous Obstruction
Venous obstruction causes tissue changes when it affects a very large vein (eg, superior vena cava) or one without adequate collaterals (eg, central vein of the retina, superior sagittal sinus, renal vein, cavernous sinus). When collateral venous drainage exists but is marginal, as in the femoral vein in the leg, occlusion may cause mild edema because of increased hydrostatic pressure at the venular end of the capillary (Chapter 2: Abnormalities of Interstitial Tissues).
In situations where collateral drainage is inadequate, congestion of the tissue occurs in addition to edema (Figure 9-2), as is seen in the face when the superior vena cava is occluded. In acute severe venous congestion, hydrostatic pressure may rise enough to cause capillary rupture and hemorrhage, eg, orbital congestion and hemorrhage in cavernous sinus occlusion. In extreme cases, venous infarction may result (see below).
Effect of venous obstruction on tissues. A: Loop of intestine drained by several veins. Obstruction of the main draining vein causes no change in the tissue because venous drainage is taken over by collaterals. B: Venous drainage of the orbit is mainly into the cavernous sinus. Venous collaterals are insufficient to compensate when there is occlusion of the cavernous sinus. Cavernous sinus thrombosis therefore results in edema, congestion, and hemorrhage in the orbit. C: The venous drainage of the testis is by numerous veins, all of which pass up the spermatic cord. Twisting (torsion) of the spermatic cord usually obstructs all the veins without initially obstructing the artery. This results in testicular edema, hemorrhage, and venous infarction.
Venous Congestion in Heart Failure
Specific types of venous congestion occur in heart failure when venous blood backs up in the circulatory system because of failure of the heart to pump all of the venous return.
Pulmonary Venous Congestion
Left heart failure causes congestion of the pulmonary circulation. Acute congestion causes dilation of alveolar capillaries with transudation of fluid into the alveoli (pulmonary edema) (Figure 9-3A). Intra-alveolar hemorrhage may also result. In chronic congestion, the long-standing increase in pulmonary venous pressure stimulates development of fibrosis in alveolar walls (Figure 9-3B). Escape of erythrocytes into alveoli over a long period causes accumulation of hemosiderin-laden macrophages (heart failure cells) in the alveoli (Figure 9-3C).
A: Acute congestion and edema of the lung in a patient with acute left ventricular failure. The alveolar septa show congestion, and the alveoli are filled with edema fluid. B: Chronic venous congestion of the lung. The alveolar septa are thickened by fibrosis, and the alveoli contain scattered hemosiderin-laden macrophages. C: Chronic venous congestion of the lung, later stage. The alveolar septa show fibrosis, and there are numerous hemosiderin-laden macrophages in the alveoli.
Hepatic Venous Congestion
Right heart failure causes congestion of the systemic circulation (Chapter 21: The Heart: I. Structure & Function; Congenital Diseases). In addition to peripheral (ankle) edema, there is dilation of the central hepatic veins and congestion of the sinusoids in the central part of the hepatic lobule (Figure 9-4). These congested, red central areas alternate with the normal paler tissue in peripheral zones and create a mottled effect (so-called nutmeg liver because of its resemblance to the cut surface of a nutmeg).
Chronic venous congestion of the liver. The central vein is distended with blood, and the central zone shows congestion and atrophy of liver cells. The midzonal hepatocytes show fatty change.
As congestion increases, hypoxia due to reduced blood flow occurs, with fatty change of liver cells that enhances the mottled appearance. The cells of the central zone of the liver lobule may eventually undergo necrosis; they are then replaced by fibrous tissue. Contraction of the centrizonal fibrous tissue alternating with the surviving peripheral zonal cells may result in a nodular liver (cardiac cirrhosis).
Venous infarction results when total occlusion of all venous drainage from a tissue occurs (eg, superior sagittal sinus thrombosis [Figure 9-5], renal vein thrombosis, superior mesenteric vein thrombosis). The result is severe edema, congestion, hemorrhage, and a progressive increase in tissue hydrostatic pressure (Figure 9-2). When tissue hydrostatic pressure increases sufficiently, arterial blood flow into the tissue is obstructed, leading to ischemia and infarction. Venous infarcts are always hemorrhagic (see Classification of Infarcts, below).
Hemorrhagic infarction of the parasagittal region of one cerebral hemisphere secondary to thrombotic occlusion of the superior sagittal sinus. Note that the sinus drains the other cerebral hemisphere as well, but in this patient there must have been an alternative route for venous drainage from the unaffected side.
Special types of venous infarction occur in strangulation, in which constriction of the neck of a hernial sac results in infarction of the contents of the sac; and torsion, where twisting of the pedicle of an organ, most commonly the testis, results in venous obstruction and hemorrhagic infarction.
Infarction is the development of an area of localized necrosis in a tissue resulting from sudden reduction of its blood supply (Figure 9-6). Both parenchymal cells and interstitial tissue undergo necrosis. Infarction is most commonly due to arterial obstruction by thrombosis or embolism. More rarely, obstruction of venous drainage results in infarction.
Bilateral renal infarction secondary to renal artery thrombosis. The infarcts are pale and wedge-shaped. Note the presence of extensive thrombosis at the bifurcation of the aorta.
Classification of Infarcts
The appearance of an infarct varies with the site. Various classification schemes are used.
Pale (white, anemic) infarcts (Figure 9-6) occur as a result of arterial obstruction in solid organs such as the heart, kidney, spleen, and brain that lack significant collateral circulation. The continuing venous drainage of blood from the ischemic tissue accounts for the pallor of such infarcts.
Red (or hemorrhagic) infarcts are found in tissues that have a double blood supply—eg, lung and liver—or in tissues such as intestine that have collateral vessels permitting some continued flow into the area although the amount is not sufficient to prevent infarction. The infarct is red because of extravasation of blood in the infarcted area from necrotic small vessels.
Red infarcts may also occur in tissue if dissolution or fragmentation of the occluding thrombus permits reestablishment of arterial flow to the infarcted area. Venous infarcts are always associated with congestion and hemorrhage. They are red infarcts (Figure 9-5).
In all tissues other than brain, infarction usually produces coagulative necrosis of cells, leading to a solid infarct (Chapter 1: Cell Degeneration & Necrosis). In brain, on the other hand, liquefactive necrosis of cells leads to the formation of a fluid mass in the area of infarction. The end result is frequently a cystic cavity (Figure 1-17).
Most infarcts are sterile. Septic infarcts are characterized by secondary bacterial infection of the necrotic tissue. Septic infarcts occur (1) when microorganisms are present in the occluding thrombus or embolus, eg, emboli in acute infective endocarditis; or (2) when infarction occurs in a tissue (eg, intestine) that normally contains bacteria; or (3) when bacteria from the bloodstream cause secondary infection (this is unusual because blood is normally sterile). Septic infarcts are characterized by acute inflammation that frequently converts the infarct to an abscess. Secondary bacterial infection of an infarct may also result in gangrene (eg, in the intestine).
Infarction occurs in tissue supplied by an artery that, when occluded, leaves an insufficient collateral blood supply (Figure 9-7). Infarcts in kidney, spleen, and lung are wedge-shaped, with the occluded artery situated near the apex of the wedge and the base of the infarct located on the surface of the organ. The characteristic shape of infarcts in these organs is due to the symmetric dichotomous branching pattern of the arteries supplying them.
Distribution of infarction in the myocardium following acute occlusion of the left anterior descending artery. In cases where collaterals have developed, the infarcted area may be much smaller.
The shape of cerebral and myocardial infarcts is irregular and determined by the distribution of the occluded artery and the limits of collateral arterial supply (Chapter 23: The Heart: III. Myocardium & Pericardium). In some patients, obstruction of the left anterior descending coronary artery results in infarction of the anterior interventricular septum, apex, and anterolateral left ventricle; in patients with extensive collaterals, the infarcted area may be much smaller. The thickness of the infarct is similarly variable. Intestinal infarcts develop in loops of bowel in accordance with the pattern of arterial supply. The most common infarcts of the intestine occur in the small intestine as a result of occlusion of the superior mesenteric artery.
Evolution of a myocardial infarct.
An infarct is an irreversible tissue injury characterized by necrosis of both parenchymal cells and the connective tissue framework. Necrosis induces an acute inflammatory response in the surrounding tissue, with congestion (forming a red rim around a pale infarct in the first few days) and neutrophil emigration (Figures 9-8 and 9-9). Lysosomal enzymes from neutrophils then cause lysis of the infarcted area (heterolysis), and macrophages phagocytose the liquefied debris. Ingrowth of granulation tissue occurs. Acute inflammatory cells are replaced by lymphocytes and macrophages as active necrosis ceases. Lymphocytes and plasma cells probably represent an immune response to the release of endogenous cellular antigens.
Myocardial infarct 2–4 days old, showing infiltration of the infarcted area by neutrophils. Note early lysis of the dead muscle fibers.
Collagen production by fibroblasts in the granulation tissue ultimately leads to scar formation. Because of contraction, the resulting scar is much smaller than the area of the original infarct. Cytokines released by chronic inflammatory cells are partly responsible for stimulating fibrosis and neovascularization (Chapter 6: Healing & Repair).
Evolution of a cerebral infarct differs from the above (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases). Necrotic cells undergo liquefaction because of their enzyme content (autolysis). Neutrophils are less conspicuous than in infarcts of other tissues. Liquefied brain cells are phagocytosed by special macrophages (microglia), which become distended with foamy, pale cytoplasm (Figure 1-18). The infarcted area is converted into a fluid-filled cystic cavity that becomes walled off by proliferation of reactive astrocytes (a process termed gliosis, which represents the cerebral analogue of fibrosis).
The rate of evolution of an infarct and the time required for complete healing vary with size. A small infarct may heal within 1–2 weeks, whereas healing of a larger one may take 6–8 weeks or longer. Evaluation of the gross and microscopic changes in an infarcted area enables the pathologist to assess the age of an infarct, which is an important consideration at autopsy in establishing the sequence of events that caused death.
Shock is a clinical state characterized by a generalized decrease in perfusion of tissues associated with decrease in effective cardiac output.
Mechanisms causing shock. Note 1: In shock resulting from a primary decrease in cardiac output, the jugular venous pressure is elevated. In shock primarily due to decreased venous return, the jugular venous pressure is reduced. Note 2: Decreased perfusion leads to changes that result in a further decrease in perfusion, thus setting up vicious cycles (eg, erythrocyte sludging, myocardial ischemia, shock lung, intestinal ischemia). These contribute to irreversible shock. Note 3: Generalized tissue hypoxia leading to progressive acidosis is thought to be a major contributing factor in irreversible shock.
Hypovolemia (Decreased Blood Volume)
Hypovolemia may be due to hemorrhage (either external or internal) or excessive fluid loss, as occurs in diarrhea, vomiting, burns, dehydration, or excessive sweating.
Widespread dilation of small vessels leads to excessive pooling of blood in peripheral capacitance vessels. The result is reduction of the effective blood volume and therefore a decreased cardiac output (peripheral circulatory failure). Peripheral vasodilation may be due to the action of metabolic, toxic, or humoral factors. More rarely, it may be caused by neurogenic stimuli, as occurs during anesthesia or spinal cord injury. Simple fainting is a form of neurogenic shock; it is normally self-correcting, because when the patient falls to the ground, the recumbent position increases venous return and thereby restores cardiac output. In septic shock, circulating endotoxin (bacterial lipopolysaccharide) binds with the CD14 receptor on macrophages, producing massive release of cytokines, particularly tumor necrosis factor (TNF), the net results of which include permeability changes and intravascular coagulation. Similar systemic permeability changes in anaphylactic shock are mediated by histamine, bradykinin, and leukotrienes released by the degranulation of mast cells and basophils (Chapter 8: Immunologic Injury).
Cardiogenic shock results from a severe reduction in cardiac output due to primary cardiac disease, eg, acute myocardial infarction, acute myocarditis, and certain arrhythmias.
Obstruction to blood flow in the heart or main pulmonary artery, as occurs in massive pulmonary embolism or a large left atrial thrombus impacting in the mitral valve orifice, causes obstructive shock. Severely impaired filling of the ventricles, as occurs in cardiac tamponade, produces a significant fall in cardiac output.
Shock develops in stages as outlined below.
Compensatory mechanisms that are activated by a decrease in cardiac output include reflex sympathetic stimulation, which increases the heart rate (tachycardia) and causes peripheral vasoconstriction that maintains blood pressure in vital organs (brain and myocardium). The earliest clinical evidence of shock is a rapid, low-volume (thready) pulse.
Peripheral vasoconstriction is most marked in less vital tissues. The skin becomes cold and clammy—another early clinical manifestation of shock. Vasoconstriction in renal arterioles decreases the pressure and rate of glomerular filtration, with resulting decreased urine output (oliguria). Oliguria represents a compensatory mechanism to retain fluid. The term prerenal uremia is used for this oliguric state resulting from causes outside the kidney; the kidney is normal, and the condition resolves rapidly when cardiac output increases.
Stage of Impaired Tissue Perfusion
Prolonged excessive vasoconstriction is harmful because it impairs tissue perfusion, impairs tissue fluid exchange and oxygenation, and leads to sludging, which further impedes capillary blood flow.
Impaired tissue perfusion has several adverse effects. It promotes anaerobic glycolysis, leading to production of lactic acid and lactic acidosis, which is almost always present in shock. Impaired tissue perfusion, if severe or sustained, produces cell necrosis, which is most apparent in the kidney; acute renal tubular necrosis occurs (Figure 9-11), resulting in acute renal failure. In the lung, hypoxia due to impaired perfusion causes acute alveolar damage with intra-alveolar edema, hemorrhage, and formation of hyaline fibrin membranes (shock lung, or adult respiratory distress syndrome [ARDS] [Figure 9-12]). In the liver, anoxic necrosis of the central region of hepatic lobules may occur. Ischemic necrosis of the intestine is important because it is frequently associated with hemorrhage or release of bacterial endotoxins that further aggravate the shock state.
Acute renal tubular necrosis involving proximal tubules.
Shock lung, showing congestion, intra-alveolar hemorrhage, and edema. Hyaline membrane formation indicates acute alveolar damage.
As shock progresses, decompensation occurs. Reflex peripheral vasoconstriction fails, probably as a result of increasing capillary hypoxia and acidosis. Widespread vasodilation and stasis result and lead to a progressive fall in blood pressure (hypotension) until perfusion of brain and myocardium sinks to a critical level. Cerebral hypoxia then causes acute brain dysfunction (loss of consciousness, edema, neuronal degeneration). Myocardial hypoxia leads to further diminution of cardiac output, and death may occur rapidly.
The prognosis for a patient in shock depends on several factors, the most important of which is the underlying cause. When this can be treated (eg, hypovolemia, which can be corrected by fluid infusion), most patients survive even if they are in an advanced stage of shock when first seen. In patients who recover, necrotic cells—eg, renal tubular cells and alveolar epithelial cells—usually regenerate, and these tissues regain normal function. Patients who die are those in whom the cause of shock cannot easily be treated (eg, massive myocardial infarction) and those for whom treatment is started after lethal tissue injury has occurred (irreversible shock).
There are four principal causes of vascular occlusion: (1) extramural compression by fibrosis or a neoplasm, eg, superior vena cava compression by a mediastinal tumor; (2) arterial spasm, which is recognized as a rare cause of ischemia in the brain and myocardium; (3) diseases of the vessel wall, including atherosclerosis and inflammation (vasculitis), which rarely cause occlusion unless complicated by thrombosis; and (4) thrombosis and embolism (see below), which are the most common causes.
Thrombosis is the formation of a solid mass from the constituents of blood (platelets, fibrin, and entrapped red and white blood cells) within the heart or vascular system in a living organism. Thrombosis is usually distinguished from blood clotting, although the distinction is somewhat arbitrary and both invoke the coagulation cascade. Clotting occurs in tissues when blood escapes from an injured vessel (hematoma formation). It also occurs in vessels after death (postmortem clotting of blood) and in vitro (in a test tube outside the body). A thrombus is generally attached to the endothelium and is composed of layers of aggregated platelets and fibrin, whereas a blood clot contains randomly oriented fibrin with entrapped platelets and red cells.
Mechanisms of normal hemostasis. A: In normal uninjured vessels, subendothelial connective tissue, especially collagen and elastin, is not exposed to the circulating blood. B: In the first few seconds after injury, exposure of subendothelial tissue attracts platelets, which adhere and aggregate at the site of injury. Endothelial injury also activates Hageman factor (factor XII), which in turn activates the intrinsic pathway of the coagulation cascade. Release of tissue thromboplastins activates the extrinsic pathway. C: Hemostasis is achieved in minutes. Platelet degranulation stimulates further platelet aggregation. Fibrin formed by activation of the coagulation cascade combines with the mass of aggregated platelets to form the definitive hemostatic plug that seals the injury. Plasmin (fibrinolysin) formed by activation of the fibrinolytic pathway prevents excessive fibrin formation. D: During healing (hours to days), the thrombus retracts, and organization and fibrosis of the thrombus occur. Reendothelialization of the vessels is the final step.
Thrombosis is a normal hemostatic mechanism that acts to stop bleeding when a vessel is injured. Under normal conditions, there is a delicate and dynamic balance between thrombus formation and dissolution of thrombus (fibrinolysis).
Following trauma, the usual initiating factor in thrombus formation is endothelial injury, which leads to formation of a hemostatic platelet plug and activation of the coagulation and fibrinolytic systems.
Formation of Hemostatic Platelet Plug
(Figure 9-14.) Injury to the vascular endothelium exposes subendothelial collagen, which has a strong thrombogenic effect on platelets and results in the adherence of platelets at the site. The platelets adhering to the injured endothelium aggregate to form a hemostatic plug, which is the beginning of a thrombus. Platelet aggregation in turn leads to degranulation of platelets, which releases serotonin, adenosine diphosphate (ADP), adenosine triphosphate (ATP), and thromboplastic substances. ADP—itself a powerful platelet aggregator—causes further accumulation of platelets. The layers of platelets alternating with fibrin in a thrombus appear on microscopic examination as pale lines (lines of Zahn) (Figure 9-15).
Effect of endothelial injury on the coagulation system and platelets, resulting in formation of the definitive hemostatic plug, or thrombus. Note that simultaneous activation of the opposing fibrinolytic system provides a degree of control over the extent of thrombus formation. (For greater detail, see Figure 27-2.)
Thrombus, showing alternating zones of amorphous platelets (lines of Zahn) and fibrillary fibrin.
(Figure 9-14.) Activation of Hageman factor (factor XII in the coagulation cascade) results in the formation of fibrin by activation of the intrinsic coagulation pathway. (For further details, see Chapter 27: Blood: IV. Bleeding Disorders.) Tissue thromboplastins released by injury activate the extrinsic coagulation pathway, which contributes to fibrin formation. Factor XIII acts on fibrin to produce an insoluble fibrillary polymer that—with the platelet plug—makes up the definitive hemostatic plug. Fibrin appears on microscopic examination as a pink-staining fibrillary meshwork intermingled with amorphous pale platelet masses (Figure 9-15).
The normal balance that exists between thrombus formation and fibrinolysis ensures that just the right amount of thrombus is formed in response to endothelial injury so that hemorrhage from the vessel is prevented. Fibrinolytic activity prevents the formation of excessive thrombus. A disturbance of this balance results in abnormal thrombosis or abnormal bleeding.
Excessive thrombus formation results in narrowing or occlusion of the vessel lumen. This usually occurs as a result of local factors at the site that overwhelm the ability of a normally functional fibrinolytic system to prevent excess thrombosis. Decreased fibrinolysis alone almost never produces excessive thrombosis.
In contrast, decreased ability to form thrombi results in excessive bleeding and occurs in a variety of bleeding disorders, including decreased platelets in the blood, deficiency of coagulation factors, and increased fibrinolytic activity. These disorders are considered in Chapter 27: Blood: IV. Bleeding Disorders.
Factors in Thrombus Formation
Endothelial damage, which stimulates both platelet adhesion and activation of the coagulation cascade, is frequently the dominant initiating factor when thrombosis occurs in the arterial circulation. When thrombosis occurs in veins and in the microcirculation, endothelial damage is less conspicuous. Changes in blood flow such as a decreased rate of flow and turbulence, and changes in the blood itself (eg, increased viscosity, increased fibrinogen levels and platelet numbers) are more important factors in venous thrombosis. The entry of thromboplastic substances into the bloodstream may cause widespread thrombosis. Thromboplastic substances are present in some snake venoms, amniotic fluid, the cytoplasmic granules of neutrophil precursors (promyelocytes), and mucin produced by certain cancer cells.
A thrombus is easily recognized as a solid mass in the lumen of a blood vessel that is often attached to the vessel wall (Figure 9-16). Thrombi in the fast-flowing arterial circulation are composed predominantly of fibrin and platelets, with few entrapped erythrocytes—hence the term pale thrombi.
Abdominal aorta, showing multiple large thrombi attached to the endothelial surface. The thrombi have alternating pale and red areas.
Red thrombi are composed of platelets, fibrin, and large numbers of erythrocytes trapped in the fibrin mesh. Red thrombi typically occur in the venous system, where the slower blood flow encourages entrapment of red cells.
Rarely, thrombi composed almost entirely of aggregated platelet masses form in patients who are receiving heparin therapy (the anticoagulant action prevents fibrin formation).
(Figures 9-16 and 9-17.) Arterial thrombosis is common and typically occurs after endothelial damage and local turbulence has been caused by atherosclerosis (Chapter 20: The Blood Vessels). Large- and medium-sized arteries such as the aorta, carotid arteries, arteries of the circle of Willis, coronary arteries, and arteries of the intestine and limbs are mainly affected.
Thrombosis in an athero-sclerotic artery. A: Normal artery, showing typical laminar blood flow. B: Atherosclerotic artery, showing atherosclerotic plaques. The endothelium is intact, but the vessel lumen is narrowed. Decreased blood flow and increased turbulence are present. C: Ulcerated atherosclerotic plaque from which fragments of the plaque have become detached and passed distally as cholesterol emboli (see Figure 9-28). Blood flow is further decreased and turbulence increased. Thrombosis has occurred over the ulcerated area. D: Extension of thrombosis has caused total occlusion of the artery, and there is no blood flow in the vessel.
Less commonly, arterial thrombosis is a complication of arteritis, as occurs in polyarteritis nodosa, giant cell arteritis, thromboangiitis obliterans, and Henoch-Schönlein purpura (Chapter 20: The Blood Vessels). Medium- and small-sized arteries are commonly affected.
Thrombi form within the chambers of the heart in the following circumstances.
Inflammation of Cardiac Valves
Endocardial damage occurring in association with inflammation of the cardiac valves (endocarditis, valvulitis) leads to local turbulence and deposition of platelets and fibrin on the valves. These thrombi are called vegetations (Figure 9-18; Chapter 22: The Heart: II. Endocardium & Cardiac Valves). Vegetations may be large and friable (as occurs in infective endocarditis), and fragments of thrombus often break off and are carried in the circulation as emboli (see below).
Vegetation (= thrombus) on mitral valve in subacute infective endocarditis.
Damage to Mural Endocardium
Myocardial infarction and ventricular aneurysms are associated with damage to the mural endocardium. Thrombi forming on the walls are often large and may also give rise to emboli.
Turbulence and Stasis in Atrial Chambers
Thrombi often form in chambers of the atrium when turbulence and stasis of blood occur, typically in patients with mitral valve stenosis or atrial fibrillation. Thrombi may be so large (ball thrombus) that they obstruct the mitral valve orifice. Fragments of atrial thrombi may become detached and form emboli.
Thrombophlebitis denotes venous thrombosis occurring secondary to acute inflammation of the vein. Thrombophlebitis is a common phenomenon in infected wounds or ulcers and characteristically involves the superficial veins of the extremities. The affected vein is firm and cord-like and shows signs of acute inflammation (pain, redness, warmth, swelling). This type of thrombus tends to be firmly attached to the vessel wall; they rarely form emboli.
Rarely, thrombophlebitis occurs in multiple superficial leg veins (thrombophlebitis migrans) in patients with visceral cancers, most commonly pancreatic and gastric cancer (Trousseau's syndrome). Mucins and other cancer cell products have been shown to possess thromboplastin-like activity.
Phlebothrombosis denotes venous thrombosis occurring in the absence of obvious inflammation. Phlebothrombosis occurs mostly in the deep veins of the leg (deep vein thrombosis). Less commonly, veins of the pelvic venous plexus are involved. Deep vein thrombosis is common and has important medical implications because the large thrombi that form in these veins are only loosely attached to the vessel wall and are often easily detached. They travel in the circulation to the heart and lung and lodge in the pulmonary arteries (pulmonary embolism [Figure 9-19]).
Pulmonary embolism. The pulmonary artery has been opened to reveal a large thromboembolus within it. Note the branching of the embolus, probably corresponding to the configuration of the vein in which it originated.
Up to 50% of patients with deep vein thrombosis show a mutation of the factor V gene, with the result that factor V is less readily degraded by activated protein C. The mutation is known as the Leiden or Q506 mutation (producing a substitution of glycine for arginine at position 506); heterozygous individuals have a tenfold increase in risk for thrombosis, and homozygous individuals a hundredfold increase.
Otherwise, factors causing deep vein thrombosis are those typical of thrombosis in general, although endothelial injury is usually minimal. Sluggish blood flow is an important factor. In the venous plexus of the calf muscles, blood flow is normally maintained by calf muscle contraction (the muscle pump). Prolonged immobilization in bed favors stasis of blood and thrombosis. The routine use of physical therapy, compressive stockings, and early ambulation after surgery has considerably decreased the incidence of postoperative deep vein thrombosis. Other factors predisposing to thrombus formation include changes in the composition of blood in postoperative or postpartum patients that result in an increased tendency toward platelet adhesion and aggregation, as well as increased levels of some coagulation factors (fibrinogen and factors VII and VIII). Oral contraceptives—particularly those with high estrogen levels—may cause increased blood coagulability. Cardiac failure also contributes to sluggish blood flow in the deep veins of the calf. In practice, several of these factors may act together.
Deep vein thrombosis of the legs may cause few or no clinical symptoms. Mild edema of the ankles and calf pain when the ankle is dorsiflexed (Homans' sign) are helpful diagnostic features. In many patients, pulmonary embolism is the first clinical manifestation of phlebothrombosis. Deep vein thrombosis can be detected by venography, ultrasonography, and other radiologic techniques.
Thrombus formation evokes a host response that is designed to remove the thrombus and repair the injured blood vessel. Several outcomes are possible.
Lysis of the thrombus (fibrinolysis) accompanied by reestablishment of the lumen is the ideal end result. The fibrin constituting the thrombus is dissolved by plasmin, which is activated by Hageman factor (factor XII) whenever the intrinsic coagulation pathway is activated (ie, the fibrinolytic system is activated at the same time as the clotting sequence; this mechanism for clot lysis is a built-in control function that normally prevents excessive thrombosis) (Figure 9-14). Fibrinolysis is effective in preventing excess fibrin formation and in dissolving small thrombi. Fibrinolysis is much less effective in dissolving large thrombi occurring in arteries, veins, or the heart itself. Drugs such as streptokinase and tissue plasminogen activator (alteplase, recombinant; tissue plasminogen activator (t-PA)), which activate the fibrinolytic system, are effective when used immediately after thrombosis in causing lysis of the thrombus and reestablishing perfusion. They have been used with some success in the treatment of acute myocardial infarction, deep vein thrombosis, and acute peripheral arterial thrombosis.
Organization and Recanalization
Organization and recanalization commonly occur in large thrombi. Slow liquefaction and phagocytosis of the thrombus are followed by ingrowth of granulation tissue and collagenization (organization). The vessels in the granulation tissue frequently enlarge and may establish new channels across the thrombus (recanalization) (Figure 9-20) through which some blood flow may be restored. Recanalization occurs slowly over several weeks, and although it does not prevent the acute effects of thrombosis, it may slightly improve tissue perfusion over the long term.
Early organization and recanalization of a thrombosed vessel. As the process progresses, the thrombus is completely replaced by collagen and the vascular channels in the granulation tissue dilate.
Sometimes a fragment of thrombus is detached and carried in the circulation to lodge at a distant site—a process termed thromboembolism (see below).
Disseminated Intravascular Coagulation (Dic)
Disseminated intravascular coagulation is the widespread development of small thrombi in the microcirculation throughout the body (Figure 9-21). It is a serious and often fatal complication of numerous diseases and requires early recognition and treatment.
Disseminated intravascular coagulation (DIC). Numerous microthrombi are seen in glomerular capillaries.
Table 9–1. Associated with Disseminated Intravascular Coagulation (DIC). ||Download (.pdf)
Table 9–1. Associated with Disseminated Intravascular Coagulation (DIC).
Disseminated fungal infections
Severe viremias (eg, hemorrhagic fevers)
Plasmodium falciparum malaria
Neonatal and intrauterine infections
Aminotic fluid embolism
Retained dead fetus
Small vessel vasculitides
Surgery with extracorporeal circulation
Snakebite (Russell's viper)
Initiating factors and mechanisms in disseminated intravascular coagulation (DIC). A key difference between DIC and normal thrombus formation is that in DIC both coagulation and fibrinolysis occur diffusely throughout the microcirculation—in contrast to the more localized nature of normal thrombosis. In some instances, thrombosis predominates, resulting in ischemic effects; in others, fibrinolysis predominates, resulting in hemorrhage.
In many cases, the cause of disseminated intravascular coagulation is unknown. Diffuse endothelial injury, as occurs in infections due to gram-negative bacteria (gram-negative sepsis, endotoxic shock), is a common cause. Viral and rickettsial infections may result in direct infection and damage to endothelial cells. Immunologic injury to the endothelium, as occurs in type II and type III hypersensitivity, may also precipitate DIC. Disseminated intravascular coagulation may occur when thromboplastic substances enter the circulation, as occurs in amniotic fluid embolism (amniotic fluid contains thromboplastin, which has procoagulant activity), snakebite (particularly Russell's viper), promyelocytic leukemia (the promyelocytes contain thromboplastic substances), and any condition associated with extensive tissue necrosis.
Decreased Tissue Perfusion
The multiple occlusions of the microcirculation in disseminated intravascular coagulation result in widespread impaired tissue perfusion, leading to shock, accumulation of lactic acid, and microinfarction in many organs. Note that the disseminated thrombi may not be demonstrable at autopsy owing to concurrent fibrinolytic activity (see below).
Disseminated thrombosis also results in the consumption of coagulation factors in the blood (consumption coagulopathy). Paradoxically, thrombocytopenia develops and, together with depletion of fibrinogen and other coagulation factors, leads to abnormal bleeding. This bleeding tendency is aggravated by excessive activation of the fibrinolytic system (activation of Hageman factor XII, which initiates the intrinsic coagulation pathway, also leads to conversion of plasminogen to plasmin). Fibrin degradation products resulting from the action of plasmin on fibrin also have anticoagulant properties, further exacerbating the bleeding tendency. In many patients with disseminated intravascular coagulation, the predominant clinical effect is hemorrhage.
Treatment includes heparin to inhibit the formation of thrombi as well as administration of platelets and plasma to restore the depleted coagulation factors. Monitoring the levels of fibrin degradation products, fibrinogen, and platelets aids diagnosis and assesses the effectiveness of therapy.
Embolism is the occlusion or obstruction of a vessel by an abnormal mass (solid, liquid, or gaseous) transported from a different site by the circulation. Most emboli are detached fragments of thrombi that are carried in the bloodstream to their sites of lodgment (thromboembolism). Numerous other substances serve as less common causes of embolism (Table 9-2).
Types of Embolism.
Types of Embolism.
Origin and Type of Embolism
Circulatory System Involved
Thrombi in right side of heart and systemic veins
Deep vein thrombosis
Circulatory arrest, lung infarction, pulmonary hypertension
Right–sided infective endocarditis
Thrombi in left side of heart and systemic arteries
Cardiac valvular vegetations
Infarction in brain, kidney, intestine, peripheral arteries
Cardiac mural thrombus
Cardiac atrial thrombus
Cardiac aneurysmal thrombus
Aortic aneurysmal thrombus
Puncture of jugular vein
Pulmonary (right ventricle)
Total obstruction of pulmonary flow causes sudden death
Childbirth or abortion
Blood transfusion using positive pressure
Nitrogen gas embolism
Pulmonary and systemic
Ischemia in lung, brain, nerves
Trauma (ie, serious fractures of large bones)
Mostly pulmonary; some fat globules pass to systemic
Microinfarcts and hemorrhages in lung, brain, skin
Bone marrow embolism
No clinical significance
Ulcerated atheromatous plaque
Microinfarction in brain, retina, kidney
Amniotic fluid embolism
Disseminated intravascular coagulation
Depends on location of tumor
The site of embolism is governed by the point of origin and size of the embolus.
Emboli that originate in systemic veins (as a result of venous thrombosis) or in the right side of the heart (eg, infective endocarditis affecting the tricuspid valve) lodge in the pulmonary arterial system unless they are so small (eg, fat globules, tumor cells) that they can pass through the pulmonary capillaries. The point of lodgment in the pulmonary arterial circulation depends on the size of the embolus (see below). Rarely, an embolus originating in a systemic vein passes across a defect in the cardiac interatrial or interventricular septum (thus bypassing the lungs) to lodge in a systemic artery (paradoxic embolism).
Emboli that originate in branches of the portal vein lodge in the liver, eg, cancer cells from colonic or pancreatic cancer.
Origin in Heart and Systemic Arteries
Emboli originating in the left side of the heart and systemic arteries (as a result of cardiac or arterial thrombosis) lodge in a distal systemic artery in sites such as the brain, heart, kidney, extremity, intestine, etc.
Types & Sites of Embolism
Detached fragments of thrombi are the most common cause of clinically significant embolism.
The most serious form of thromboembolism is pulmonary embolism, which may cause sudden death. About 600,000 patients per year develop clinically evident pulmonary embolism in the United States; about 100,000 of them die. Over 90% of pulmonary emboli originate in the deep veins of the leg (phlebothrombosis). More rarely, thrombi in pelvic venous plexuses are the source. Pulmonary embolism is common in the following conditions that predispose to the development of phlebothrombosis: (1) The immediate postoperative period. About 30–50% of patients show evidence of deep vein thrombosis after major surgery. Only a small number of these patients develop clinically significant pulmonary embolism. (2) The immediate postpartum period. (3) Lengthy immobilization in bed. (4) Cardiac failure. (5) Use of oral contraceptives.
(Figure 9-23.) The size of the embolus is the factor most influencing the clinical effects of pulmonary embolism.
Clinical effects of pulmonary embolism. A: Massive pulmonary embolism causes circulatory arrest and sudden death (Figure 9-24). B: A large embolism occluding one pulmonary artery may cause pulmonary infarction or sudden death due to reflex vasoconstriction of the pulmonary circulation (see Figure 9-19). Some healthy individuals may show no ill effects, but this is unusual with a large embolus. C: A small to medium-sized embolus in a pulmonary arterial branch typically has no effect in healthy individuals. Pulmonary infarction may occur if the bronchial circulation is compromised, as in patients with left heart failure and pulmonary hypertension. D: Small emboli have no effect unless they are numerous, in which case they may cause pulmonary hypertension.
Massive pulmonary embolism. The main pulmonary artery has been opened and shows impacted thromboemboli at the orifices of both right and left main pulmonary arteries. This led to sudden death from circulatory obstruction. Note: When the pulmonary arteries were further opened, the emboli were seen to be very large. Only their tips are shown here.
Massive emboli–Large emboli (several centimeters long and of the same diameter as the femoral vein) may lodge in the outflow tract of the right ventricle or in the main pulmonary artery, where they cause circulatory obstruction and sudden death (Figure 9-24). Large emboli lodging in a large branch of the pulmonary artery may also cause sudden death, probably as a result of severe vasoconstriction of the entire pulmonary arterial circulation induced reflexly by lodgment of the embolus (Figure 9-19).
Medium-sized emboli–Moderate-sized emboli often lodge in a major branch of the pulmonary artery. In healthy individuals, the bronchial artery supplies blood (and oxygen) to the lung, and the function of the pulmonary artery is mainly gas exchange (not local tissue oxygenation). In a normal person, therefore, a moderate-sized pulmonary embolus creates an area of lung that is ventilated but not perfused with regard to gas exchange. This results in abnormal gas exchange and hypoxemia, but infarction of the lung does not occur. In a patient with chronic left heart failure or pulmonary vascular disease, however, the bronchial arterial circulation is impaired, and the lung is therefore dependent on the pulmonary artery for perfusion of tissue as well as gas exchange. In these patients, obstruction of a pulmonary artery by a moderate-sized embolus results in pulmonary infarction.
Small emboli–Small emboli lodge in minor branches of the pulmonary artery with no immediate effects (Figure 9-25). In many instances, the emboli either fragment soon after lodgment or dissolve during fibrinolysis, in which case clinical effects are minimal. If numerous small emboli occur over a long period, however, the pulmonary microcirculation may be so severely compromised that pulmonary hypertension results.
Pulmonary thromboembolism partially occluding a small branch of the pulmonary artery in the lung. This has no immediate effect, but pulmonary hypertension may result if recurrent and numerous emboli occur.
Systemic Arterial Embolism
Thromboembolism occurs in systemic arteries when the detached thrombus originates in the left side of the heart or a large artery. Systemic arterial thromboembolism commonly occurs (1) in patients who have infective endocarditis with vegetations on the mitral and aortic valves; (2) in patients who have suffered myocardial infarction in which mural thrombosis has occurred; (3) in patients with mitral stenosis and atrial fibrillation due to left atrial thrombosis; and (4) in patients with aortic and ventricular aneurysms, which often contain mural thrombi. Thromboemboli from any of these locations pass distally to lodge in an artery of some other organ. Because of the anatomy of the aorta, cardiac emboli tend to pass more frequently into the lower extremities or into the circulation derived from the right internal carotid artery than into other systemic arteries.
The clinical effects of systemic thromboembolism are governed by the size of the obstructed vessel, the availability of collateral arterial circulation, and the susceptibility of the tissue to ischemia (see Factors Influencing the Effect of Arterial Obstruction, above). Infarction is common when emboli lodge in the arteries of the brain, heart, kidney, and spleen. Infarction occurs in the intestine and lower extremities only when large arteries are occluded or when the collateral circulation in these tissues is compromised.
Air embolism occurs when enough air bubbles enter the vascular system to produce clinical symptoms; about 150 mL of air causes death. The condition is rare.
Surgery of or Trauma to Internal Jugular Vein
In injuries to the internal jugular vein, the negative pressure in the thorax tends to suck air into the jugular vein. This phenomenon does not occur in injuries to other systemic veins because they are separated by valves from the negative pressure in the chest.
Air embolism may occur during childbirth or abortion, when air may be forced into ruptured placental venous sinuses by the forceful contractions of the uterus.
Air embolism during blood transfusions occurs only if positive pressure is used to transfuse the blood and only if the transfusion is inadvertently not discontinued at its completion. The use of collapsible plastic packs for blood transfusion has greatly reduced the risk of this catastrophe.
When air enters the bloodstream, it passes into the right ventricle, creating a frothy mixture that effectively obstructs the circulation and causes death. More rarely, the frothy air-blood mixture obstructs a pulmonary artery.
Nitrogen Gas Embolism (Decompression Sickness)
Decompression sickness is a form of embolism that occurs in caisson workers and undersea divers if they ascend too rapidly after being submerged for long periods. The disorder is also called the bends or caisson disease (caissons are high-pressure underwater chambers used for deep water construction work). When air is breathed under high underwater pressure, an increased volume of air, mainly oxygen and nitrogen, goes into solution in the blood and equilibrates with the tissues.
If decompression to sea level is too rapid, the gases that have equilibrated in the tissues come out of solution. Oxygen is rapidly absorbed into the blood, but nitrogen gas coming out of solution cannot be absorbed rapidly enough and forms bubbles in the tissues and bloodstream that act as emboli.
Scuba divers breathing high-pressure compressed air who ascend rapidly from depths as shallow as 10 m may also develop decompression sickness, and those who engage in this recreational activity should be taught and cautioned to ascend slowly.
Decompression sickness can also occur in unpressurized aircraft if they ascend too rapidly to high altitudes (above 2000 m). Mountain climbers who climb too rapidly to high altitudes are also at risk.
Platelets adhere to nitrogen gas bubbles in the circulation and activate the coagulation cascade. The resulting disseminated intravascular thrombosis aggravates the ischemic state caused by impaction of gas bubbles in capillaries. Involvement of the brain in severe cases may cause extensive necrosis and death. In less severe cases, nerve and muscle involvement causes severe muscle contractions with intense pain (the bends). Nitrogen gas emboli in the lungs cause severe difficulty in breathing (the chokes) that is associated with alveolar edema and hemorrhage.
Fat embolism occurs when globules of fat enter the bloodstream, typically after fractures of large bones (eg, femur) have exposed the fatty bone marrow. Rarely, extensive injury to subcutaneous adipose tissue causes fat embolism. Although fat globules can be found in the circulation in as many as 90% of patients who have sustained serious fractures, few patients demonstrate clinically significant signs of fat embolism.
Although simple mechanical rupture of fat cells at trauma sites may explain how fat globules can enter the circulation, other factors are probably involved. It has been shown that fat globules enlarge once they are in the circulation, which explains why small globules that bypass lung capillaries may later become obstructed in systemic capillaries. It is thought that release of catecholamines due to the stress of trauma mobilizes free fatty acids, which coalesce to form progressively enlarging fat globules. Adhesion of platelets to fat globules further increases their size and causes thrombosis. When this process is extensive, it is equivalent to disseminated intravascular coagulation.
Circulating fat globules first encounter the capillary network of the lung. Larger fat globules (> 20 μm) are arrested in the lung and cause respiratory distress (dyspnea and abnormal gas exchange). Smaller fat globules escape the lung capillaries and pass into the systemic circulation, where they may obstruct small systemic arteries. Typical clinical features of fat embolism include a hemorrhagic skin rash and brain involvement manifested as acute diffuse neurologic dysfunction.
The possibility of fat embolism must be considered if respiratory distress, cerebral dysfunction, and a hemorrhagic rash occurs 1–3 days after major trauma. The diagnosis can be confirmed by demonstrating fat globules in urine and sputum. About 10% of patients with clinical fat embolism die. At autopsy, fat globules can be demonstrated in many organs using frozen sections and special fat stains (eg, oil red O).
Fragments of bone marrow containing fat and hematopoietic cells may enter the circulation after traumatic injury of bone marrow and may be found in the pulmonary arteries of patients who have suffered rib fractures during cardiopulmonary resuscitative efforts. Bone marrow embolism is of no clinical significance.
Atheromatous (Cholesterol) Embolism
Large ulcerated atheromatous plaques often release cholesterol and other atheromatous material into the circulation (Figure 9-26). Emboli are carried distally to lodge in small systemic arteries. Such embolization in brain produces transient ischemic attacks, characterized by reversible acute episodes of neurologic dysfunction.
Cholesterol embolus derived from an ulcerated atheromatous plaque lodged in a branch of the renal artery.
The contents of the amniotic sac may rarely (1:80,000 pregnancies) enter ruptured uterine venous sinuses during tumultuous labor in childbirth. Although rare, amniotic fluid embolism is associated with a mortality rate of about 80% and is a significant cause of maternal deaths in the United States.
Amniotic fluid is rich in thromboplastic substances that induce disseminated intravascular coagulation, which is the main mechanism by which the disorder is manifested clinically. Amniotic fluid also contains fetal squamous epithelium (desquamated from the skin), fetal hair, fetal fat, mucin, and meconium, all of which may undergo embolization and become lodged in the pulmonary capillaries, a finding that is useful in making an autopsy diagnosis of amniotic fluid embolism (Figure 9-27).
Amniotic fluid embolism of lung.
Cancer cells often enter the circulation during metastasis of malignant tumors (see Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms). Typically, these solitary cells or small clumps of cells are too small to obstruct the vasculature. Occasionally, larger fragments of tumor constitute significant emboli—with renal carcinoma, especially in the inferior vena cava; and with hepatic carcinoma, especially in the hepatic veins.